The overall objective of this proposal is to identify, map and characterize genetic factors affecting lipoprotein metabolism using a mouse animal model. During the previous five years, we have examined genes and proteins involved in lipid metabolism in the mouse and have identified and partially characterized a number of genetic variations affecting the levels and structures of lipoproteins. This proposal is directed at the further development of the mouse animal model and the molecular-genetic characterization of several polymorphisms of particular interest that have been identified in surveys of inbred strains of mice. Among these polymorphisms are the following: (i) Mutations of the apo AII structural locus that affect HDL size and apolipo-protein composition. (ii) Mutations of the Ath-1 gene which affect HDL levels in response to a high fat diet and also susceptibility to aortic intimal lipidosis. (iii) Mutations which control the levels and structures of LDL and VLDL particles on both chow and high fat diets. (iv) Mutations which control the tissue-specific expression of lipoprotein lipase. (v)Mutations which determine the levels of apo AIV mRNA and which affect the induction of apo AIV mRNA levels in response to a high fat diet challenge. Several of these naturally occurring polymorphisms in mice may prove to be valuable models for human polymorphisms.